C L I N I C A L F O C U S : P A I N M A N A G E M E N T, R A R E D I S E A S E S , A N D A L L E R G I E S

Optimal Treatment of Anaphylaxis: Antihistamines Versus Epinephrine

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DOI: 10.3810/pgm.2014.07.2785

Stanley M. Fineman, MD Adjunct Associate Professor, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA; Atlanta Allergy and Asthma Clinic, Marietta, GA

Abstract: Anaphylaxis is a rapid, systemic, often unanticipated, and potentially life-threatening immune reaction occurring after exposure to certain foreign substances. The main immunologic triggers include food, insect venom, and medications. Multiple immunologic pathways underlie anaphylaxis, but most involve immune activation and release of immunomodulators. Anaphylaxis can be difficult to recognize clinically, making differential diagnosis key. The incidence of anaphylaxis has at least doubled during the past few decades, and in the United States alone, an estimated 1500 fatalities are attributed to anaphylaxis annually. The increasing incidence and potentially life-threatening nature of anaphylaxis coupled with diagnostic challenges make appropriate and timely treatment critical. Epinephrine is universally recommended as the first-line therapy for anaphylaxis, and early treatment is critical to prevent a potentially fatal outcome. Despite the evidence and guideline recommendations supporting its use for anaphylaxis, epinephrine remains underused. Data indicate that antihistamines are more commonly used to treat patients with anaphylaxis. Although histamine is involved in anaphylaxis, treatment with antihistamines does not relieve or prevent all of the pathophysiological symptoms of anaphylaxis, including the more serious complications such as airway obstruction, hypotension, and shock. Additionally, antihistamines do not act as rapidly as epinephrine; maximal plasma concentrations are reached between 1 and 3 hours for antihistamines compared with , 10 minutes for intramuscular epinephrine injection. This demonstrates the need for improved approaches to educate physicians and patients regarding the appropriate treatment of anaphylaxis. Keywords: anaphylaxis; antihistamines; epinephrine; first-line treatment

Introduction

Correspondence: Stanley M. Fineman, MD, Atlanta Allergy and Asthma Clinic, 895 Canton Road, Building 200, Suite 200, Marietta, GA 30060. Tel: 770-427-1471 Fax: 770-424-2280 E-mail: [email protected]

Anaphylaxis is a rapid, systemic, often unanticipated, and potentially fatal immune reaction occurring after exposure to certain foreign substances (ie, antigens).1,2 The main immunologic triggers include food, insect venom, and medications; however, the extent to which these triggers contribute to anaphylaxis varies depending on study design, study population, and geographic area.3 In the United States and Europe, food is typically the primary contributor and accounts for approximately 32% to 56% of cases overall3–7; however, among older adults (ie, aged . 50 years), food-associated anaphylaxis is much less frequent than in children and younger adults.8 In Asia and Latin America, medications are more common triggers for anaphylaxis than foods.9,10 Less common immunologic triggers include latex, immunotherapy, and environmental allergens.3–5 Nonimmunologic triggers, such as exercise, cold exposure, radiocontrast materials, nonsteroidal anti-inflammatory drugs, and opioids, can also cause anaphylaxis.3,11 Unknown triggers are responsible for approximately 20% of anaphylactic events.3

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Stanley M. Fineman

According to a recent consensus definition, which takes into account epidemiologic, research, and clinical needs, a diagnosis of anaphylaxis should be considered if any 1 of 3 specific criteria occurs within minutes to hours of exposure to a foreign substance (Table 1).1 The onset and specific signs and symptoms of an anaphylactic episode vary depending on the sensitivity of the person exposed and the absorption rate, route, and quantity of the allergen.12 The majority of reactions are immediate and occur within minutes of exposure; however, a small proportion of reactions may also be biphasic,13 whereby the initial symptoms wane for a period of time and then recur.14–18 Additionally, because of the diversity of immune mediators involved in anaphylaxis, several organ systems can be affected, including the skin, respiratory tract, gastrointestinal tract, cardiovascular system, and central nervous system.3,19,20 Multiple factors contribute to the difficulty of differentially diagnosing anaphylaxis in the clinic. Diagnosis can be especially challenging during an initial episode; if the trigger is a novel agent; if noncutaneous symptoms predominate; or if anaphylaxis occurs in an infant, young child, or unconscious individual.21–24 Certain clinical situations, such as an asthmatic event, hemodialysis, and undergoing anesthesia while in surgery, can also complicate the diagnosis.25–28 Furthermore, anaphylaxis can occasionally be confused with septic or other forms of shock, airway obstruction due to a foreign body, or panic attack.29 In most cases, given the emergency nature of anaphylaxis, a diagnosis is based on clinical symptoms and patient history.19

Table 1.  Consensus Definition of Anaphylaxis Anaphylaxis should be considered if any 1 of the following 3 criteria occurs within minutes to hours of exposure to a foreign substance: 1. Acute onset of illness with cutaneous and/or mucosal involvement AND at least 1 of the following:   a. Respiratory compromise (eg, dyspnea, bronchospasm, stridor, hypoxia)   b. Cardiovascular compromise (eg, hypotension, collapse) 2. Two or more of the following:   a. Involvement of skin or mucosa (eg, generalized hives, itch, flushing, swelling)   b. Respiratory compromise   c. Cardiovascular compromise   d. Persistent gastrointestinal symptoms (eg, abdominal cramping, vomiting) 3. H  ypotension: age-specific low blood pressure or . 30% decline from baseline Reprinted from Sampson HA, Muñoz-Furlong A, Campbell RL, et al. Second symposium on the definition and management of anaphylaxis: summary report— second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47(4):373–380 with permission from Elsevier.

74

However, laboratory tests can also aid in proper diagnosis in specific circumstances, including uncertain presentations of symptoms.20,30–33 Although plasma histamine levels increase during anaphylaxis, evaluating serum histamine for the diagnosis of anaphylaxis is impractical, given that levels only remain elevated for 30 to 60 minutes.21,34 Evaluating serum tryptase is likely more realistic because levels peak 60 to 90 minutes after onset and remain elevated for up to 5 hours.29,34 Measurement of total tryptase concentrations in serum or plasma is currently the most widely used laboratory test for the diagnosis of anaphylaxis. Elevated levels are not commonly found in individuals with foodinduced anaphylaxis; thus, low levels of tryptase do not rule out a diagnosis of anaphylaxis.21,35 Serial tryptase measurements may be helpful to improve sensitivity of detection of an anaphylactic reaction, particularly in patients whose tryptase levels are only moderately elevated (ie, patients who are experiencing reactions to drugs or insect venom).36,37 Finally, some patients with anaphylaxis have increased levels of histamine or tryptase but not both.29 Although studies assessing the incidence of anaphylaxis are limited, often imprecise, and likely underestimate the actual prevalence, most concur that the incidence has at least doubled across age groups during the past few decades, with an estimated lifetime prevalence ranging from 0.05% to 2% in North America, Europe, and Australia.3,7,38–40 Over the last decade, this increase may be as high as 350% for food-induced cases and 230% for non–food-induced cases in some countries.41 Up to 20% of individuals with anaphylaxis have a second episode, and between 5% and 13% have a third episode.5,40 In the United States alone, an estimated 1500 fatalities per year are attributed to anaphylaxis42; in the United Kingdom and Australia, the rates of fatal anaphylactic reactions have been estimated at 0.33 per million per year and 0.64 per million per year, respectively.43 The increasing incidence and potentially life-threatening nature of anaphylaxis coupled with diagnostic challenges make appropriate and timely treatment critical. Clinical evidence and guideline recommendations indicate that epinephrine should be the first-line therapy for anaphylaxis19,20,44–48; however, data indicate that other treatments, including antihistamines, corticosteroids, and bronchodilators, are often more commonly used than epinephrine to treat patients with anaphylaxis.44 This review focuses on the misuse of antihistamines as a first-line therapy for anaphylaxis; they are frequently selected for treatment because of the role of histamine in anaphylaxis.44 However, a thorough examination of anaphylaxis pathophysiology

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Epinephrine and Antihistamines for Anaphylaxis

and the respective mechanisms of action of antihistamines and epinephrine provide a strong, evidence-based rationale for the use of epinephrine versus antihistamines for optimal treatment of anaphylaxis.

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Pathophysiology of Anaphylaxis

Anaphylaxis is a multifactorial response in which multiple immunologic mechanisms may be involved in a single episode.21 The typical pathway/mechanism of anaphylaxis results from immunoglobulin E–mediated activation of mast cells and basophils.3,21,38 Exposure to allergens causes cross-linking of immunoglobulin (Ig) E molecules and activation of the FcεR1 receptors on the surface of mast cells and basophils.38 Upon activation, mast cells and basophils release various preformed immunologic mediators such as histamine, heparin, tryptase, chymase, carboxypeptidase A3, tumor necrosis factor-α, and cathepsin G as well as newly formed immunologic mediators including platelet-activating factor (PAF); prostaglandin D2; leukotriene C4; cytokines such as interleukin (IL)-5, IL-6, IL-8, IL-13, and granulocytemacrophage colony-stimulating factor; and chemokines such as macrophage inflammatory protein-1α and -1β, and monocyte chemoattractant protein-1 (Figure 1).21 In addition, activated mast cells can trigger a complement cascade via release of trypsin and kallikrein.38 Interestingly, some allergens (eg, nonsteroidal anti-inflammatory drugs/aspirin or radiocontrast materials) can activate the complement cascade directly.21 Of note, individuals with elevated numbers of mast cells are more prone to anaphylaxis or anaphylaxis-type symptoms.21 More severe anaphylaxis (eg, presenting with hypotension, hypoxia, and symptoms involving $ 3 organ systems) has also been linked to the use of antihypertensive medications such as β-blockers and angiotensin-converting enzyme inhibitors.49 Histamine plays a key role in the pathophysiology of anaphylaxis.3,38,50,51 Following allergen exposure, histamine levels are higher than most other allergen-stimulated immune modulators, and the effects of histamine are mediated by various histamine receptors. Currently, 4 subclasses of histamine receptors have been identified. Coronary vasoconstriction and bronchial constriction occur through the H1 receptor; systemic vasodilation, gastric acid secretion, and cardiac contractility are mediated by the H2 receptor; neurotransmission is regulated by the H3 receptor; and immune cell activation occurs via the H4 receptor.3,50 Both the H1 and H2 receptors regulate hypotension, tachycardia, flushing, and headache, and the H1 and H3 receptors modulate nasal congestion and cutaneous itch.51

However, histamine is not the only immune factor to play an important role in anaphylaxis.3,38 Of the newly formed immunologic mediators, PAF has recently been shown to play a major role in anaphylaxis. A study demonstrated that mean serum PAF levels are significantly higher in patients with anaphylaxis than in control patients (P , 0.001) and also differ by grade of anaphylaxis reaction.52 The proportion of patients with elevated PAF levels increased from 4% in control patients to 20% in those with grade 1 anaphylaxis (acute allergic reactions with cutaneous involvement only), 71% in those with grade 2 anaphylaxis (mild-to-moderate manifestations of anaphylaxis, including decrease in systolic blood pressure), and 100% in those with grade 3 anaphylaxis (severe manifestations of anaphylaxis, including life-threatening respiratory and cardiovascular signs; P , 0.001).52 Data also suggest that PAF may mediate an amplification loop for mast cell activation in anaphylaxis.38 Other factors involved in anaphylaxis include tryptase, immune aggregates, IgG, IgM, platelets, and T cells.38 As described previously, determining serum tryptase levels can be a useful diagnostic tool to identify anaphylaxis.30,31,33

Antihistamines: Inadequate for Treatment of Anaphylaxis

Because histamine plays a key role in the pathophysiology of anaphylaxis, H1-antihistamines (eg, diphenhydramine, fexofenadine, hydroxyzine, cetirizine) and H2-antihistamines such as ranitidine are frequently used for the treatment of anaphylaxis.44 In a national study of 12.4 million US emergency department visits for anaphylaxis from 1993 to 2004, H1-antihistamines were prescribed in 59% to 62% of cases, and H2-antihistamine prescriptions increased from 7% to 18%.53 Another retrospective study found that 72% and 61% of patients with anaphylaxis who visited an Australian emergency department were treated with H1- and H2-antihistamines, respectively.54 In a pediatric study of patients presenting to an Australian emergency department, 51% and 5% of children were found to be treated with H1- and H2-antihistamines, respectively.55 Data from the anaphylaxis registry of German-speaking countries reveal that antihistamines were the most frequently used (50%) emergency therapy for anaphylaxis in children and adolescents between 2006 and 2010.56 However, H1- and H2-antihistamines do not target all of the underlying mechanisms of anaphylaxis, and although they are assumed to be effective on the basis of theoretical reasoning and misconceptions in popular culture, their efficacy for the treatment of anaphylaxis is not supported by randomized controlled clinical trials. A Cochrane systematic

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Stanley M. Fineman

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Figure 1.  Mast cells and basophils generate several products upon activation during anaphylaxis.

Reprinted from Simons FE, Frew AJ, Ansotegui IJ, et al. Risk assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol. 2007;120(1 suppl):S2–S24 with permission from Elsevier. Abbreviations: GM-CSF, granulocyte-macrophage colony-stimulating factor; IgE, immunoglobulin E; IL, interleukin; MIP-1α, macrophage inflammatory protein 1α; TNFα, tumor necrosis factor α.

review of 2070 studies found no high-quality evidence from randomized controlled trials without methodological issues to support the use of H1-antihistamines in anaphylaxis.57 In addition, a systematic review on the use of H2-antihistamines for the treatment of anaphylaxis failed to identify any randomized controlled trials that could be used to support their use as first-line agents.58 As described above, histamine is not the only regulator of anaphylaxis, and data show that the use of antihistamines is inadequate to fully control the array of symptoms, some life-threatening, associated with an anaphylactic response. H1-antihistamines may help to relieve itching, flushing, hives, and nasal symptoms (Figure 2)44,51,59; however, they do not relieve or prevent the more serious complications of anaphylaxis, such as airway obstruction, hypotension, or shock.44 H2-antihistamines, which are only used in combination with H1-antihistamines for anaphylaxis, may be effective at reducing hives and tachycardia but have no significant effect on itching or other symptoms.44 76

In addition to limited effectiveness, there are pharmacokinetic considerations that make the use of antihistamines in anaphylaxis inadequate. H1-antihistamines have a slow absorption and relatively long time of onset of action. The average maximal plasma concentration of H1-antihistamines does not occur until 1 to 3 hours after oral administration.51,60,61

Epinephrine:The Optimal Initial Therapy for Anaphylaxis

Epinephrine is a direct-acting α- and β-adrenergic agonist with multiple systemic actions mediated by various receptors.62 On the basis of its mechanism of action, there are multiple physiologic benefits of epinephrine in anaphylaxis (Figure 3).62,63 For example, epinephrine can stimulate α-adrenoceptors, leading to increased peripheral vascular resistance, which in turn improves blood pressure and coronary perfusion and decreases angioedema. Epinephrine also targets β1-adrenoceptors, leading to improvement in

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Epinephrine and Antihistamines for Anaphylaxis

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Figure 2.  H1- and H2-antihistamines relieve some symptoms of anaphylaxis by antagonizing the H1- and H2-receptors, respectively.

Abbreviations: Ca, calcium; NF-κB, nuclear factor kappa-B.

cardiac contractility and heart rate. Additionally, activation of β2-adrenoceptors via epinephrine causes bronchodilation and increased intracellular cyclic adenosine monophosphate production in mast cells and basophils, which can reduce mediator release. Not only does epinephrine target the underlying pathophysiology of anaphylaxis, available treatment guidelines from the American Academy of Allergy, Asthma, and Immunology, the American College of Allergy, Asthma, and Immunology, the European Academy of Allergy and Clinical Immunology, the Australasian Society of Clinical Immunology and Allergy, and the World Allergy Organization (WAO) published in indexed peer-reviewed journals unanimously recommend epinephrine as first-line therapy for anaphylaxis on the basis of human experience and expert opinion (Table 2).19,20,44–47 Understandably, there is reluctance to perform randomized controlled trials in anaphylaxis patients because of ethical, clinical, and logistical considerations. As with antihistamines, 2 systematic reviews, including a Cochrane analysis, did not find any adequate, controlled clinical trials to support any new recommendations in addition to the current recommended use of epinephrine as first-line therapy for anaphylaxis.64,65 However, even without randomized controlled trials, the evidence base for epinephrine use in anaphylaxis is stronger than that for other medications, such as antihistamines.65 First-line treatment with epinephrine for acute anaphylaxis is firmly recommended on the basis of other types of studies (eg, prospective, nonrandomized, uncontrolled studies; retrospective studies; analyses of emergency department visits; population-based

cohort and survey studies; and nonsystematic clinical observations) and expert opinion. Furthermore, evidence from fatalities due to delayed use or no use of epinephrine during an anaphylactic event is considered particularly strong support for the early use of epinephrine in cases of severe anaphylaxis. This includes analyses reporting the use of epinephrine in only 14% of patients before circulatory or respiratory arrest, and a lack of epinephrine administration in a majority of patients immediately after or within an hour of onset of symptoms.35,66,67 Individuals who experience severe anaphylaxis require immediate pharmacologic assistance, and all available guidelines are in agreement that treatment with epinephrine should not be delayed.19,20,44–47 The median time to respiratory or cardiac arrest after exposure to an allergen may be 5 to 30 minutes depending on the type of allergen.66 Therefore, the most commonly recommended route of epinephrine administration is intramuscular injection because of its rapid absorption.68–70 Furthermore, peak plasma concentrations of epinephrine injected intramuscularly into the thigh have been shown to be significantly higher (P , 0.01) than those of epinephrine injected subcutaneously or intramuscularly into the upper arm.70 The rapid absorption time of epinephrine is in stark contrast to the time antihistamines need to reach maximal plasma concentration (1–3 hours).51,60,61 A recent study reviewing electronic records of children presenting with anaphylaxis to an urban pediatric emergency department (PED) between 2004 and 2008 demonstrated that administration of epinephrine before arrival to the PED was associated with a lower rate of hospitalization compared with administration

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Figure 3.  Epinephrine is a direct-acting α- and β-adrenergic agonist.

of epinephrine in the PED (P = 0.05).22 This study highlights the benefit of early treatment with epinephrine. The majority of individuals who die from anaphylaxis have not received an epinephrine injection, and delay in epinephrine injection can result in mortality or increased hospital stay.22,35,66,71–75 In addition to being effective, intramuscular administration of epinephrine is generally safe and associated with a low risk of major complications or serious adverse events. Most adverse events associated with epinephrine occur after overdose or with intravenous administration.63 Intravenous injection should be reserved for patients with unresponsive anaphylaxis and should only be administered by specialists trained in dose titration of vasopressors.44,63 Frequent and appropriate monitoring of blood pressure, heart rate, respiratory status, and oxygenation is also recommended.20 Importantly, there are no contraindications to intramuscular epinephrine use in anaphylaxis.62 Additionally, unintentional injection of epinephrine produced no long-term sequelae,76 suggesting the risk associated with intramuscular administration of epinephrine is far lower than the potentially life-threatening risk of not using epinephrine during an anaphylactic reaction. Despite the scientific evidence and support from guidelines, the data suggest that epinephrine is both underused by 78

patients and underprescribed by physicians in the treatment of anaphylaxis. Multiple factors have been cited by patients as reasons for the underuse of epinephrine, including lack of affordability or access, substitution with other medications (eg, antihistamines), one’s first experience with anaphylaxis was mild or it resolved without epinephrine, fear of injection, and not knowing when it is appropriate to use epinephrine.77 Additionally, a national survey revealed poor overall preparedness for future anaphylactic reactions among patients with a history of anaphylaxis: 34% of patients reported that their plan for future anaphylactic episodes included use of an epinephrine autoinjector, 37% of patients planned to take an antihistamine, and 42% of patients had no anaphylaxis emergency plan.40 This survey also reported that 50% of patients with a history of anaphylaxis had never been prescribed an autoinjector, highlighting the underprescribing of epinephrine by physicians.40 In a national study of US emergency department visits for anaphylaxis, epinephrine prescriptions actually declined from 19% to 7% from 1993 to 2004.53 In the anaphylaxis registry of German-speaking countries (described above), epinephrine was used in only 13% of cases between 2006 and 2010, and intramuscular epinephrine was used in only 3.9% of cases.56

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Epinephrine and Antihistamines for Anaphylaxis

Table 2.  Treatment Guidelines: Epinephrine as First-Line Therapy for Anaphylaxisa,b Guidelines

Use of Epinephrine

United States United Kingdom

IM or SCc 1:1000 dilution; adult dose, 0.2–0.5 mg; repeat at 5-min intervals; IV infusion IM 0.01 mg/kg; adult dose, 0.5 mg; repeat at 5-min intervals; IM route has greater margin of safety than IV route, which should be used only by experienced specialists IM 0.01 mg/kg, to a maximum of 0.5 mg; repeat at 3- to 5-min intervals; IV infusion per hospital protocol only if cardiac arrest is imminent; nebulization (in addition to injected epinephrine) for persistent stridor IM 0.01 mg/kg, to a maximum of 0.5 mg, repeat at 5- to 10-min intervals; IV infusion (restrictions apply); nebulization (restrictions apply) IM 0.01 mg/kg, to a maximum dose of 0.5 mg (0.3 mg in children), repeat at 5- to 15-min intervals

Australia EAACI (pediatric) WAO

The rationale for selecting the guidelines listed in this table is that they are published in indexed peer-reviewed journals and used beyond the countries in which they were developed; for example, the US guidelines are used throughout North America and Latin America, the UK guidelines are used in other European countries, and the Australian guidelines are used throughout southeast Asia. b Different systems of grading the quality of the evidence and the strength of the recommendations are used in the US, UK, Australian, and EAACI guidelines. c The participants at the Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network Symposium stated that available evidence indicated intramuscular administration is preferred over subcutaneous injection. Adapted from Simons FE. Pharmacologic treatment of anaphylaxis: can the evidence base be strengthened? Curr Opin Allergy Clin Immunol. 2010;10(4):384–393. Reprinted with permission from Lippincott Williams & Wilkins, Inc. Abbreviations: EAACI, European Academy of Allergy and Clinical Immunology; IM, intramuscular; SC, subcutaneous; WAO, World Allergy Organization.

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a

Conclusion

Anaphylaxis is a rapid and potentially life-threatening reaction that requires immediate pharmacologic intervention. Multiple physiologic pathways underlie anaphylaxis, but most involve immune activation and release of immunomodulators. Epinephrine is universally recommended as the first-line therapy for anaphylaxis, and early treatment is critical to prevent a potentially fatal outcome. Despite the body of evidence and guideline recommendations supporting the use of epinephrine for first-line treatment of anaphylaxis, the data suggest that epinephrine is underused. Conversely, even though there is a lack of evidence for the use of antihistamines for the treatment of anaphylaxis, these agents are still commonly used in patients with anaphylaxis. In addition to not addressing all of the underlying symptoms of anaphylaxis, prompt treatment of anaphylaxis is not achieved with the use of antihistamines because maximal plasma concentrations are reached between 1 and 3 hours for antihistamines compared with , 10 minutes for intramuscular epinephrine injection. This suggests the need for improved educational approaches to increase adherence to anaphylaxis guidelines and to enhance physicians’ understanding of the mechanisms of anaphylaxis and the reasons why epinephrine should be considered the only first-line treatment. Improved physician education will enable physicians to communicate optimal anaphylaxis management strategies to their patients, which include establishing straightforward anaphylaxis emergency plans, emphasizing the importance of always carrying an epinephrine autoinjector, and appropriately training patients on the use of epinephrine autoinjectors to address patients’ feelings of uncertainty or fear.

Acknowledgments

Editorial assistance was provided, under the direction of the author, by Todd Parker, PhD, Charlene Rivera, PhD, and Jennifer Rossi at MedThink SciCom, with support from Mylan Specialty LP.

Conflict of Interest Statement

Stanley M. Fineman, MD, has received research support from Genentech, Meda, Shionogi, and Sunovion, and has served on speakers’ bureaus for and/or has received consulting fees from AstraZeneca, Genentech/Novartis, Meda, Mylan, and Sunovion.

References 1. Sampson HA, Muñoz-Furlong A, Campbell RL, et  al. Second symposium on the definition and management of anaphylaxis: summary report—second National Institute of Allergy and Infectious Disease/ Food Allergy and Anaphylaxis Network symposium. Ann Emerg Med. 2006;47(4):373–380. 2. Simons FE, Sheikh A. Anaphylaxis: the acute episode and beyond. BMJ. 2013;346:f602. 3. Ben-Shoshan M, Clarke AE. Anaphylaxis: past, present and future. Allergy. 2011;66(1):1–14. 4. Bohlke K, Davis RL, DeStefano F, et al. Epidemiology of anaphylaxis among children and adolescents enrolled in a health maintenance organization. J Allergy Clin Immunol. 2004;113(3):536–542. 5. Decker WW, Campbell RL, Manivannan V, et  al. The etiology and incidence of anaphylaxis in Rochester, Minnesota: a report from the Rochester Epidemiology Project. J Allergy Clin Immunol. 2008;122(6):1161–1165. 6. Beyer K, Eckermann O, Hompes S, Grabenhenrich L, Worm M. Anaphylaxis in an emergency setting—elicitors, therapy and incidence of severe allergic reactions. Allergy. 2012;67(11):1451–1456. 7. Panesar SS, Javad S, de Silva D, et al. The epidemiology of anaphylaxis in Europe: a systematic review. Allergy. 2013;68(11):1353–1361.

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Stanley M. Fineman 8. Campbell RL, Hagan JB, Li JT, et al. Anaphylaxis in emergency department patients 50 or 65 years or older. Ann Allergy Asthma Immunol. 2011;106(5):401–406. 9. Hsin YC, Hsin YC, Huang JL, Yeh KW. Clinical features of adult and pediatric anaphylaxis in Taiwan. Asian Pac J Allergy Immunol. 2011;29(4):307–312. 10. Solé D, Ivancevich JC, Borges MS, et al. Anaphylaxis in Latin America: a report of the online Latin American survey on anaphylaxis (OLASA). Clinics (Sao Paulo). 2011;66(6):943–947. 11. Wölbing F, Fischer J, Köberle M, Kaesler S, Biedermann T. About the role and underlying mechanisms of cofactors in anaphylaxis. Allergy. 2013;68(9):1085–1092. 12. Bochner BS, Lichtenstein LM. Anaphylaxis. N Engl J Med. 1991;324(25):1785–1790. 13. Rohacek M, Edenhofer H, Bircher A, Bingisser R. Biphasic anaphylactic reactions: occurrence and mortality. Allergy. 2014;69(6):791–797. 14. Brazil E, MacNamara AF. “Not so immediate” hypersensitivity— the danger of biphasic anaphylactic reactions. J Accid Emerg Med. 1998;15(4):252–253. 15. Ellis AK, Day JH. Incidence and characteristics of biphasic anaphylaxis: a prospective evaluation of 103 patients. Ann Allergy Asthma Immunol. 2007;98(1):64–69. 16. Lieberman P. Biphasic anaphylactic reactions. Ann Allergy Asthma Immunol. 2005;95(3):217–226. 17. Stark BJ, Sullivan TJ. Biphasic and protracted anaphylaxis. J Allergy Clin Immunol. 1986;78(1, pt 1):76–83. 18. Lee JM, Greenes DS. Biphasic anaphylactic reactions in pediatrics. Pediatrics. 2000;106(4):762–766. 19. Lieberman P, Nicklas RA, Oppenheimer J, et  al. The diagnosis and management of anaphylaxis practice parameter: 2010 update. J Allergy Clin Immunol. 2010;126(3):477–480. 20. Simons FE, Ardusso LR, Bilò MB, et al. World Allergy Organization guidelines for the assessment and management of anaphylaxis. World Allergy Organ J. 2011;4(2):13–37. 21. Simons FE, Frew AJ, Ansotegui IJ, et al. Risk assessment in anaphylaxis: current and future approaches. J Allergy Clin Immunol. 2007;120(Suppl 1): S2–S24. 22. Huang F, Chawla K, Järvinen KM, Nowak-Węgrzyn A. Anaphylaxis in a New York City pediatric emergency department: triggers, treatments, and outcomes. J Allergy Clin Immunol. 2012;129(1):162–168. 23. Rudders SA, Banerji A, Clark S, Camargo CA Jr. Age-related differences in the clinical presentation of food-induced anaphylaxis. J Pediatr. 2011;158(2):326–328. 24. Topal E, Bakirtas A, Yilmaz O, et al. Anaphylaxis in infancy compared with older children. Allergy Asthma Proc. 2013;34(3):233–238. 25. Thong BY, Yeow C. Anaphylaxis during surgical and interventional procedures. Ann Allergy Asthma Immunol. 2004;92(6):619–628. 26. Gurrieri C, Weingarten TN, Martin DP, et al. Allergic reactions during anesthesia at a large United States referral center. Anesth Analg. 2011;113(5):1202–1212. 27. Rainbow J, Browne GJ. Fatal asthma or anaphylaxis? Emerg Med J. 2002;19(5):415–417. 28. Wai Y, Tsui V, Peng Z, Richardson R, Oreopoulos D, Tarlo SM. Anaphylaxis from topical bovine thrombin (Thrombostat) during haemodialysis and evaluation of sensitization among a dialysis population. Clin Exp Allergy. 2003;33(12):1730–1734. 29. Tang AW. A practical guide to anaphylaxis. Am Fam Physician. 2003;68(7):1325–1332. 30. Komarow HD, Hu Z, Brittain E, Uzzaman A, Gaskins D, Metcalfe DD. Serum tryptase levels in atopic and nonatopic children. J Allergy Clin Immunol. 2009;124(4):845–848. 31. Schwartz LB. Diagnostic value of tryptase in anaphylaxis and mastocytosis. Immunol Allergy Clin North Am. 2006;26(3):451–463. 32. Stone SF, Cotterell C, Isbister GK, Holdgate A, Brown SG, for the Emergency Department Anaphylaxis Investigators. Elevated serum cytokines during human anaphylaxis: identification of potential mediators of acute allergic reactions. J Allergy Clin Immunol. 2009;124(4):786–792.

80

33. Tanus T, Mines D, Atkins PC, Levinson AI. Serum tryptase in idiopathic anaphylaxis: a case report and review of the literature. Ann Emerg Med. 1994;24(1):104–107. 34. Schwartz LB, Yunginger JW, Miller J, Bokhari R, Dull D. Time course of appearance and disappearance of human mast cell tryptase in the circulation after anaphylaxis. J Clin Invest. 1989;83(5):1551–1555. 35. Sampson HA, Mendelson L, Rosen JP. Fatal and near-fatal anaphylactic reactions to food in children and adolescents. N Engl J Med. 1992;327(6):380–384. 36. Brown SG, Blackman KE, Heddle RJ. Can serum mast cell tryptase help diagnose anaphylaxis? Emerg Med Australas. 2004;16(2):120–124. 37. Ordoqui E, Zubeldia JM, Aranzábal A, et al. Serum tryptase levels in adverse drug reactions. Allergy. 1997;52(11):1102–1105. 38. Lee JK, Vadas P. Anaphylaxis: mechanisms and management. Clin Exp Allergy. 2011;41(7):923–938. 39. Lieberman P, Camargo CA Jr, Bohlke K, et al. Epidemiology of anaphylaxis: findings of the American College of Allergy, Asthma and Immunology Epidemiology of Anaphylaxis Working Group. Ann Allergy Asthma Immunol. 2006;97(5):596–602. 40. Wood RA, Camargo CA Jr, Lieberman P, et al. Anaphylaxis in America: the prevalence and characteristics of anaphylaxis in the United States. J Allergy Clin Immunol. 2014;133(2):461–467. 41. Liew WK, Williamson E, Tang ML. Anaphylaxis fatalities and admissions in Australia. J Allergy Clin Immunol. 2009;123(2):434–442. 42. Neugut AI, Ghatak AT, Miller RL. Anaphylaxis in the United States: an investigation into its epidemiology. Arch Intern Med. 2001;161(1):15–21. 43. Tang ML, Osborne N, Allen K. Epidemiology of anaphylaxis. Curr Opin Allergy Clin Immunol. 2009;9(4):351–356. 44. Simons FE. Pharmacologic treatment of anaphylaxis: can the evidence base be strengthened? Curr Opin Allergy Clin Immunol. 2010;10(4):384–393. 45. Simons FE, Ardusso LR, Dimov V, et al. World Allergy Organization anaphylaxis guidelines: 2013 update of the evidence base. Int Arch Allergy Immunol. 2013;162(3):193–204. 46. Alrasbi M, Sheikh A. Comparison of international guidelines for the emergency medical management of anaphylaxis. Allergy. 2007;62(8):838–841. 47. Acute Management of Anaphylaxis Guidelines 2013. Australasian Society of Clinical Immunology and Allergy. http://www.allergy.org.au/images/ stories/pospapers/ASCIA_Acute_Management_of_Anaphylaxis_ Guidelines_September_2013.pdf. Accessed June 2, 2014. 48. Zilberstein J, McCurdy MT, Winters ME. Anaphylaxis [published online ahead of print May 29, 2014]. J Emerg Med. doi:10.1016/j. jemermed.2014.04.018. 49. Lee S, Hess EP, Nestler DM, et al. Antihypertensive medication use is associated with increased organ system involvement and hospitalization in emergency department patients with anaphylaxis. J Allergy Clin Immunol. 2013;131(4):1103–1108. 50. Parsons ME, Ganellin CR. Histamine and its receptors. Br J Pharmacol. 2006;147(Suppl 1):S127–S135. 51. Simons FE. Advances in H1-antihistamines. N Engl J Med. 2004; 351(21):2203–2217. 52. Vadas P, Gold M, Perelman B, et al. Platelet-activating factor, PAF acetylhydrolase, and severe anaphylaxis. N Engl J Med. 2008;358(1):28–35. 53. Gaeta TJ, Clark S, Pelletier AJ, Camargo CA. National study of US emergency department visits for acute allergic reactions, 1993 to 2004. Ann Allergy Asthma Immunol. 2007;98(4):360–365. 54. Brown AF, McKinnon D, Chu K. Emergency department anaphylaxis: a review of 142 patients in a single year. J Allergy Clin Immunol. 2001;108(5):861–866. 55. Braganza SC, Acworth JP, McKinnon DR, Peake JE, Brown AF. Paediatric emergency department anaphylaxis: different patterns from adults. Arch Dis Child. 2006;91(2):159–163. 56. Grabenhenrich L, Hompes S, Gough H, et al. Implementation of anaphylaxis management guidelines: a register-based study. PLoS One. 2012;7(5):e35778.

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Epinephrine and Antihistamines for Anaphylaxis 57. Sheikh A, Ten Broek V, Brown SG, Simons FE. H1-antihistamines for the treatment of anaphylaxis: Cochrane systematic review. Allergy. 2007;62(8):830–837. 58. Nurmatov UB, Rhatigan E, Simons FE, Sheikh A. H2-antihistamines for the treatment of anaphylaxis with and without shock: a systematic review. Ann Allergy Asthma Immunol. 2014;112(2):126–131. 59. Jauregui I, Ferrer M, Montoro J, et al. Antihistamines in the treatment of chronic urticaria. J Investig Allergol Clin Immunol. 2007;17(Suppl 2): 41–52. 60. Simons FE, Silver NA, Gu X, Simons KJ. Skin concentrations of H1-receptor antagonists. J Allergy Clin Immunol. 2001;107(3):526–530. 61. Simons FE, Silver NA, Gu X, Simons KJ. Clinical pharmacology of H 1-antihistamines in the skin. J Allergy Clin Immunol. 2002;110(5):777–783. 62. Simons FE. First-aid treatment of anaphylaxis to food: focus on epinephrine. J Allergy Clin Immunol. 2004;113(5):837–844. 63. McLean-Tooke AP, Bethune CA, Fay AC, Spickett GP. Adrenaline in the treatment of anaphylaxis: what is the evidence? BMJ. 2003;327(7427):1332–1335. 64. Sheikh A, Simons FE, Barbour V, Worth A. Adrenaline auto-injectors for the treatment of anaphylaxis with and without cardiovascular collapse in the community. Cochrane Database Syst Rev. 2012;8:CD008935. 65. Dhami S, Panesar SS, Roberts G, et al. Management of anaphylaxis: a systematic review. Allergy. 2014;69(2):168–175. 66. Pumphrey RS. Lessons for management of anaphylaxis from a study of fatal reactions. Clin Exp Allergy. 2000;30(8):1144–1150. 67. Yunginger JW, Sweeney KG, Sturner WQ, et al. Fatal food-induced anaphylaxis. JAMA. 1988;260(10):1450–1452. 68. Edwards ES, Gunn R, Simons ER, et al. Bioavailability of epinephrine from Auvi-Q compared with EpiPen. Ann Allergy Asthma Immunol. 2013;111(2):132–137.

69. Simons FE, Roberts JR, Gu X, Simons KJ. Epinephrine absorption in children with a history of anaphylaxis. J Allergy Clin Immunol. 1998;101(1, pt 1):33–37. 70. Simons FE, Gu X, Simons KJ. Epinephrine absorption in adults: intramuscular versus subcutaneous injection. J Allergy Clin Immunol. 2001;108(5):871–873. 71. Pumphrey R. Anaphylaxis: can we tell who is at risk of a fatal reaction? Curr Opin Allergy Clin Immunol. 2004;4(4):285–290. 72. Bernstein DI, Wanner M, Borish L, Liss GM, for the Immunotherapy Committee, American Academy of Allergy, Asthma and Immunology. Twelve-year survey of fatal reactions to allergen injections and skin testing: 1990–2001. J Allergy Clin Immunol. 2004;113(6):1129–1136. 73. Levy MB, Goldberg MR, Nachshon L, Tabachnik E, Katz Y. Lessons from cases of mortality due to food allergy in Israel: cow’s milk protein should be considered a potentially fatal allergen. Isr Med Assoc J. 2012;14(1):29–33. 74. Bock SA, Muñoz-Furlong A, Sampson HA. Further fatalities caused by anaphylactic reactions to food, 2001–2006. J Allergy Clin Immunol. 2007;119(4):1016–1018. 75. Pumphrey RS, Gowland MH. Further fatal allergic reactions to food in the United Kingdom, 1999–2006. J Allergy Clin Immunol. 2007;119(4):1018–1019. 76. Simons FE, Lieberman PL, Read EJ Jr, Edwards ES. Hazards of unintentional injection of epinephrine from autoinjectors: a systematic review. Ann Allergy Asthma Immunol. 2009;102(4):282–287. 77. Simons FE, Clark S, Camargo CA Jr. Anaphylaxis in the community: learning from the survivors. J Allergy Clin Immunol. 2009;124(2):301–306.

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Optimal treatment of anaphylaxis: antihistamines versus epinephrine.

Anaphylaxis is a rapid, systemic, often unanticipated, and potentially life-threatening immune reaction occurring after exposure to certain foreign su...
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